Crystalline forms of 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea  maleate

ABSTRACT

This invention relates to a crystalline form of 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate, and to pharmaceutical compositions thereof, to intermediates and methods for the production and isolation of such crystalline forms and compositions, and to methods of using such crystalline forms and compositions in the treatment of abnormal cell growth in mammals, especially humans.

FIELD OF THE INVENTION

This invention relates to a crystalline form of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureamaleate and to pharmaceutical compositions thereof, to intermediates andmethods for the production and isolation of such crystalline forms andcompositions, and to methods of using such crystalline forms andcompositions in the treatment of abnormal cell growth in mammals,especially humans.

BACKGROUND OF THE INVENTION

The monomaleate salt of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureahas the structure of Formula (I):

The compound1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea(PF-04449913) has been assigned the International Nonproprietary Name(INN) glasdegib, as described in WHO Drug Information, Vol. 29, No. 1,page 89 (2015), referencing the alternative chemical nameN-[(2R,4R)-2-(1H-benzoimidazol-2-yl)-1-methylpiperidin-4-yl]-N′-(4-cyanophenyl)urea.The maleate salt of Formula (I) may also be referred to herein as1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureamaleate or glasdegib maleate.

Preparation of glasdegib as a hydrochloride salt is described inInternational Patent Application No. PCT/IB2008/001575, published as WO2009/004427, and in U.S. Pat. Nos. 8,148,401 and 8,431,597, the contentsof each of which are incorporated herein by reference in their entirety.

Glasdegib is an inhibitor of the smoothened receptor (Smo), a componentof the hedgehog (Hh) signaling pathway that is a potential therapeutictarget in a number of human cancers, in particular hematologicmalignancies including acute myeloid leukemia (AML), acute lymphoblasticleukemia (ALL), chronic myelomonocytic leukemia (CMML), myelofibrosis(MF) and myelodysplastic syndromes (MDS). The discovery of glasdegib andits preparation as a dihydrochloride monohydrate salt has been describedby Munchhof et al. (Med. Chem., Lett, 2012, 3:106-111). A process forthe asymmetric synthesis of glasdegib has been described by Peng et al.(Org. Lett., 2014, 16:860-863).

The present invention provides crystalline glasdegib maleate havingimproved properties, such as improved chemical and thermal stabilityupon storage, and decreased hygroscopicity, while maintaining chemicaland enantiomeric stability.

The invention also provides a crystalline glasdegib imidazole complex(1:1) and a crystalline glasdegib (S)-mandelate salt, which are usefulfor the preparation of glasdegib maleate and other salts in high yieldand with high chemical purity.

SUMMARY OF THE INVENTION

Each of the embodiments described below can be combined with any otherembodiment described herein not inconsistent with the embodiment withwhich it is combined.

In one aspect, the invention provides a crystalline form of glasdegibmaleate. In a particular aspect, the invention provides a crystallineglasdegib maleate (Form 1), as further described herein.

In particular embodiments of each of the aspects of the invention, thecrystalline glasdegib maleate (Form 1) is characterized by one or moreof the following methods: (1) powder X-ray diffraction (PXRD) (2θ); (2)Raman spectroscopy (cm⁻¹); or (3) ¹³C solid state NMR spectroscopy(ppm).

In another aspect, the invention provides crystalline glasdegib maleate(Form 1), which is characterized by having:

(1) a powder X-ray diffraction (PXRD) pattern (2θ) comprising: (a) one,two, three, four, five, or more than five peaks selected from the groupconsisting of the peaks in Table 1 in °2θ±0.2 °2θ; (b) one, two or threepeaks selected from the group consisting of the characteristic peaks inTable 1 in °2θ±0.2 °2θ; or (c) peaks at 2θ values essentially the sameas shown in FIG. 1; or

(2) a Raman spectrum comprising: (a) one, two, three, four, five, ormore than five wavenumber (cm⁻¹) values selected from the groupconsisting of the values in Table 2 in cm⁻¹±2 cm⁻¹; (b) one, two, three,four, five, or more than five wavenumber (cm⁻¹) values selected from thegroup consisting of the characteristic values in Table 2 in cm⁻¹±2 cm⁻¹;or (c) wavenumber (cm⁻¹) values essentially the same as shown in FIG. 2;or

(3) a ¹³C solid state NMR spectrum (ppm) comprising: (a) one, two,three, four, five, or more than five resonance (ppm) values selectedfrom the group consisting of the values in Table 3 in ppm±0.2 ppm; (b)one, two or three resonance (ppm) values selected from the groupconsisting of the characteristic values in Table 3 in ppm±0.2 ppm; or(c) resonance (ppm) values essentially the same as shown in FIG. 3;

or a combination of any two or three of the foregoing embodiments(1)(a)-(c), (2)(a)-(c) or (3)(a)-(c), provided they are not inconsistentwith each other.

In another aspect, the invention further provides a pharmaceuticalcomposition comprising a crystalline glasdegib maleate (Form 1),according to any of the aspects or embodiments described herein, and apharmaceutically acceptable excipient.

In another aspect, the invention provides a method of treating abnormalcell growth in a mammal, including a human, comprising administering tothe mammal a therapeutically effective amount of crystalline glasdegibmaleate (Form 1).

In another aspect, the invention provides a method of treating abnormalcell growth in a mammal, including a human, comprising administering tothe mammal a therapeutically effective amount of a pharmaceuticalcomposition of the present invention comprising a crystalline glasdegibmaleate (Form 1), according to any of the aspects or embodimentsdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. PXRD pattern of crystalline glasdegib maleate (Form 1).

FIG. 2. FT-Raman spectrum of crystalline glasdegib maleate (Form 1).

FIG. 3. ¹³C solid state NMR spectrum of crystalline glasdegib maleate(Form 1).

FIG. 4. PXRD pattern of crystalline glasdegib imidazole complex (1:1).

FIG. 5. PXRD pattern of crystalline glasdegib (S)-mandelate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of the embodiments of the invention andthe Examples included herein. It is to be understood that theterminology used herein is for the purpose of describing specificembodiments only and is not intended to be limiting. It is further to beunderstood that unless specifically defined herein, the terminology usedherein is to be given its traditional meaning as known in the relevantart.

As used herein, the singular form “a”, “an”, and “the” include pluralreferences unless indicated otherwise. For example, “a” substituentincludes one or more substituents.

As used herein, unless otherwise indicated, the term “abnormal cellgrowth” refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition).

As used herein, unless otherwise indicated, the term “treat” or“treating” means reversing, alleviating, inhibiting the progress of, orpreventing the disorder or condition to which such term applies, or oneor more symptoms of such disorder or condition. The term “treatment”, asused herein, unless otherwise indicated, refers to the act of treatingas “treating” is defined immediately above.

The term “about” as used herein means having a value falling within anaccepted standard of error of the mean, when considered by one ofordinary skill in the art, for example ±20%, preferably ±10% or morepreferably ±5% of the mean.

As used herein, the term “essentially the same” means that variabilitytypical for a particular method is taken into account. For example, withreference to X-ray diffraction peak positions, the term “essentially thesame” means that typical variability in peak position and intensity aretaken into account. One skilled in the art will appreciate that the peakpositions (2θ) will show some variability, typically as much as ±0.2°.Further, one skilled in the art will appreciate that relative peakintensities will show inter-apparatus variability as well as variabilitydue to degree of crystallinity, preferred orientation, prepared samplesurface, and other factors known to those skilled in the art and shouldbe taken as qualitative measures only. Similarly, Raman spectrumwavenumber (cm⁻¹) values show variability, typically as much as ±2 cm⁻¹,while ¹³C and ¹⁹F solid state NMR spectrum (ppm) show variability,typically as much as ±0.2 ppm.

The term “crystalline” as used herein, means having a regularlyrepeating arrangement of molecules or external face planes. Crystallineforms may differ with respect to thermodynamic stability, physicalparameters, x-ray structure and preparation processes.

The invention described herein suitably may be practiced in the absenceof any element(s) not specifically disclosed herein. Thus, for example,in each instance herein any of the terms “comprising”, “consistingessentially of”, and “consisting of” may be replaced with either of theother two terms.

In some embodiments of each of the aspects of the invention, thecrystalline glasdegib maleate (Form 1) is characterized by its powderX-ray diffraction (PXRD) pattern. In other embodiments of each of theaspects of the invention, the crystalline glasdegib maleate (Form 1) ischaracterized by its Raman spectrum. In other embodiments of each of theaspects of the invention, the crystalline glasdegib maleate (Form 1) ischaracterized by its ¹³C solid state NMR spectrum.

In further embodiments, the crystalline form is characterized by acombination of two or more of these methods.

Crystalline Glasdegib Maleate (Form 1)

In one aspect, the invention provides a crystalline glasdegib maleate(Form 1).

In some embodiments, glasdegib maleate (Form 1) has a PXRD patterncomprising a peak at 2θ value of: 11.6 °2θ±0.2 °2θ. In anotherembodiment, Form 1 has a PXRD pattern comprising a peak at 2θ value of:12.1 °2θ±0.2 °2θ. In another embodiment, Form 1 has a PXRD patterncomprising a peak at 2θ value of: 19.6 °2θ±0.2 °2θ. In anotherembodiment, Form 1 has a PXRD pattern comprising a peak at 2θ value of:17.0 °2θ±0.2 °2θ. In another embodiment, Form 1 has a PXRD patterncomprising a peak at 2θ value of: 17.7 °2θ±0.2 °2θ. In anotherembodiment, Form 1 has a PXRD pattern comprising peaks at 2θ values of:11.6 and 12.1 °2θ±0.2 °2θ. In another embodiment, Form 1 has a PXRDpattern comprising peaks at 2θ values of: 11.6 and 19.6 °2θ±0.2 °2θ. Inanother embodiment, Form 1 has a PXRD pattern comprising peaks at 2θvalues of: 12.1 and 19.6 °2θ±0.2 °2θ. In another embodiment, Form 1 hasa PXRD pattern comprising peaks at 2θ values of: 11.6, 12.1 and 19.6°2θ±0.2 °2θ. In yet another embodiment, Form 1 has a PXRD patterncomprising peaks at 2θ values of: 11.6, 12.1, 17.0, 17.7 and 19.6°2θ±0.2 °2θ.

In specific embodiments, glasdegib maleate (Form 1) has a PXRD patterncomprising: (a) one, two, three, four, five, or more than five peaksselected from the group consisting of the peaks in Table 1 in °2θ±0.2°2θ; (b) one, two, three, four, five or six characteristic peaksselected from the group consisting of the peaks in Table 1; or (c) peaksat 2θ values essentially the same as shown in FIG. 1.

In some embodiments, glasdegib maleate (Form 1) has a Raman spectrumcomprising wavenumber (cm⁻¹) value of: 2219 cm⁻¹±2 cm⁻¹. In otherembodiments, Form 1 has a Raman spectrum comprising wavenumber (cm⁻¹)value of: 1612 cm⁻¹±2 cm ⁻¹. In another embodiment, Form 1 has a Ramanspectrum comprising wavenumber (cm⁻¹) value of: 1534 cm⁻¹±2 cm⁻¹. Inanother embodiment, Form 1 has a Raman spectrum comprising wavenumber(cm⁻¹) value of: 1175 cm⁻¹±2 cm⁻¹. In other embodiments, Form 1 has aRaman spectrum comprising wavenumber (cm⁻¹) values of: 1612 and 2219cm⁻¹±2 cm⁻¹. In other embodiments, Form 1 has a Raman spectrumcomprising wavenumber (cm⁻¹) values of: 1534 and 2219 cm⁻¹±2 cm⁻¹. Infurther embodiments, Form 1 has a Raman spectrum comprising wavenumber(cm⁻¹) values of: 1534, 1612 and 2219 cm⁻¹±2 cm⁻¹. In furtherembodiments, Form 1 has a Raman spectrum comprising wavenumber (cm⁻¹)values of: 1175, 1534, 1612 and 2219 cm⁻¹±2 cm ⁻¹.

In specific embodiments, glasdegib maleate (Form 1) has a Raman spectrumcomprising: (a) one, two, three, four, five, or more than fivewavenumber (cm⁻¹) values selected from the group consisting of thevalues in Table 2 in cm⁻¹±2 cm⁻¹; (b) one, two, three, four, five, ormore than five wavenumber (cm⁻¹) values selected from the groupconsisting of the characteristic values in Table 2 in cm⁻¹±2 cm⁻¹; or(c) wavenumber (cm⁻¹) values essentially the same as shown in FIG. 2.

In some embodiments, glasdegib maleate (Form 1) has a ¹³C solid stateNMR spectrum comprising the resonance (ppm) values of: 57.8 ppm±0.2 ppm.In another embodiment, Form 1 has a ¹³C solid state NMR spectrumcomprising the resonance (ppm) values of: 134.8 ppm±0.2 ppm. In anotherembodiment, Form 1 has a ¹³C solid state NMR spectrum comprising theresonance (ppm) values of: 144.7 ppm±0.2 ppm. In another embodiment,Form 1 has a ¹³C solid state NMR spectrum comprising the resonance (ppm)values of: 148.3 ppm±0.2 ppm. In another embodiment, Form 1 has a ¹³Csolid state NMR spectrum comprising the resonance (ppm) values of: 57.8and 134.8 ppm±0.2 ppm. In another embodiment, Form 1 has a ¹³C solidstate NMR spectrum comprising the resonance (ppm) values of: 57.8 and144.7 ppm±0.2 ppm. In another embodiment, Form 1 has a ¹³C solid stateNMR spectrum comprising the resonance (ppm) values of: 57.8 and 148.3ppm±0.2 ppm. In another embodiment, Form 1 has a ¹³C solid state NMRspectrum comprising the resonance (ppm) values of: 134.8 and 144.7ppm±0.2 ppm. In another embodiment, Form 1 has a ¹³C solid state NMRspectrum comprising the resonance (ppm) values of: 134.8 and 148.3ppm±0.2 ppm. In another embodiment, Form 1 has a ¹³C solid state NMRspectrum comprising the resonance (ppm) values of: 144.7 and 148.3ppm±0.2 ppm. In a further embodiment, Form 1 has a ¹³C solid state NMRspectrum comprising the resonance (ppm) values of: 57.8, 134.8 and 144.7ppm±0.2 ppm. In a further embodiment, Form 1 has a ¹³C solid state NMRspectrum comprising the resonance (ppm) values of: 57.8, 134.8 and 148.3ppm±0.2 ppm. In a further embodiment, Form 1 has a ¹³C solid state NMRspectrum comprising the resonance (ppm) values of: 57.8, 134.8, 144.7and 148.3 ppm±0.2 ppm.

In specific embodiments, glasdegib maleate (Form 1) has a ¹³C solidstate NMR spectrum (ppm) comprising: (a) one, two, three, four, five, ormore than five resonance (ppm) values selected from the group consistingof the values in Table 3 in ppm±0.2 ppm; (b) one, two or three resonance(ppm) values selected from the group consisting of the characteristicvalues in Table 3 in ppm±0.2 ppm; or (c) resonance (ppm) valuesessentially the same as shown in FIG. 3.

In further embodiments, glasdegib maleate (Form 1) is characterized by acombination of any two or three of the embodiments described above withrespect to Form 1 that are not inconsistent with each other. Exemplaryembodiments that may be used to uniquely characterize the crystallineForm 1 are provided below.

In one embodiment, Form 1 has: (a) a powder X-ray diffraction patterncomprising a peak at a 2θvalue of: 11.6 and 12.1 °2θ±0.2 °2θ; and (b) aRaman spectrum comprising wavenumber (cm⁻¹) values of: 1612 and 2219cm⁻¹±2 cm⁻¹.

In one embodiment, Form 1 has: (a) a powder X-ray diffraction patterncomprising a peak at a 2θ value of: 11.6 and 12.1 °2θ±0.2 °2θ; (b) aRaman spectrum comprising wavenumber (cm⁻¹) values of: 1612 and 2219cm⁻¹±2 cm⁻¹; and (c) a ¹³C solid state NMR spectrum comprising aresonance (ppm) value of: 148.3 ppm±0.2 ppm.

In one another embodiment, Form 1 has: (a) a Raman spectrum comprisingwavenumber (cm⁻¹) values of: 1612 and 2219 cm⁻¹±2 cm⁻¹; and (b) a ¹³Csolid state NMR spectrum comprising a resonance (ppm) value of: 148.3ppm±0.2 ppm.

In one embodiment, Form 1 has: (a) a powder X-ray diffraction patterncomprising a peak at a 2θ value of: 11.6 and 19.6 °2θ±0.2 °2θ; and (b) a¹³C solid state NMR spectrum comprising a resonance (ppm) value of:148.3 ppm±0.2 ppm.

In a further embodiment, Form 1 has: (a) a powder X-ray diffractionpattern comprising a peak at a 2θ value of: 19.6 °2θ±0.2 °2θ; (b) aRaman spectrum comprising wavenumber (cm⁻¹) values of: 2219 cm⁻¹±2 cm⁻¹;and (c) a ¹³C solid state NMR spectrum comprising a resonance (ppm)value of: 148.3 ppm±0.2 ppm.

In another aspect, the invention provides glasdegib as a 1:1 complexwith imidazole. The imidazole complex is isolable in high chemical yieldand purity and may be useful to purge impurities formed during chemicalsynthesis prior to formation of glasdegib maleate. In a further aspect,the invention provides a process for preparing glasdegib maleatecomprising treating the glasdegib imidazole complex (1:1) with maleicacid, thereby providing the salt. In another aspect, the inventionprovides glasdegib maleate (Form 1) prepared from the glasdegibimidazole complex according to the process described.

In another aspect, the invention provides the glasdegib (S)-mandelatesalt. The mandelate salt is isolable in high chemical yield and purityand may also be useful to purge impurities formed during chemicalsynthesis. The mandelate salt can be prepared in situ during the finalisolation and purification of the compounds or by separately reactingglasdegib free base with mandelic acid and isolating the salt thusformed. Thereafter, the salt may be reconverted to the free base formand then reacted with a sufficient amount of maleic acid to produce theglasdegib maleate salt in the conventional manner.

In another aspect, the invention provides a pharmaceutical compositioncomprising a crystalline glasdegib maleate (Form 1) according to any ofthe aspects or embodiments described herein, and a pharmaceuticallyacceptable excipient.

Pharmaceutical compositions of the present invention may, for example,be in a form suitable for oral administration as a tablet, capsule,pill, powder, sustained release formulations, solution, or suspension,for parenteral injection as a sterile solution, suspension or emulsion,for topical administration as an ointment or cream or for rectaladministration as a suppository. The pharmaceutical composition may bein unit dosage forms suitable for single administration of precisedosages. The pharmaceutical composition will include a conventionalpharmaceutical carrier or excipient and an active pharmaceuticalingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions containing active compounds in sterile aqueous solutions,for example, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials includelactose or milk sugar and high molecular weight polyethylene glycols.When aqueous suspensions or elixirs are desired for oral administrationthe active compound therein may be combined with various sweetening orflavoring agents, coloring matters or dyes and, if desired, emulsifyingagents or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

EXAMPLES

The examples and preparations provided below further illustrate andexemplify particular aspects and embodiments of the invention. It is tobe understood that the scope of the present invention is not limited bythe scope of the following examples.

General Method 1. Powder X-ray Diffraction (PXRD)

Powder X-ray diffraction analysis was conducted using a Bruker AXS D8ADVANCE diffractometer equipped with a Cu radiation source (K-αaverage). The system is equipped with a 2.5 axial Soller slits on theprimary side. The secondary side utilizes 2.5 axial Soller slits andmotorized slits. Diffracted radiation was detected by a Lynx Eye XEdetector. The X-ray tube voltage and amperage were set to 40 kV and 40mA respectively. Data was collected in the Theta-Theta goniometer at theCu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of0.037 degrees and a step time of 1920 seconds. Samples were prepared byplacing them in a low background holder and rotated during collection.Data were collected using Bruker DIFFRAC Plus software (Version 9.0.0.2)and analysis was performed by EVA diffract plus software.

The PXRD data file was not processed prior to peak searching. Using thepeak search algorithm in the EVA software, peaks selected with athreshold value of 1 and a width value of 0.3 were used to makepreliminary peak assignments. The output of automated assignments wasvisually checked to ensure validity and adjustments were manually madeif necessary. Peaks with relative intensity of ≧2% were generallychosen. The peaks which were not resolved or were consistent with noisewere not selected. A typical variability associated with the peakposition from PXRD is +/−0.2° 2-Theta.

General Method 2. FT-Raman

Raman spectra were collected using a Nicolet NXR FT-Raman accessoryattached to the FT-IR bench. The spectrometer is equipped with a 1064 nmNd:YVO4 laser and a liquid nitrogen cooled Germanium detector. Prior todata acquisition, instrument performance and calibration verificationswere conducted using polystyrene. Samples were analyzed in glass NMRtubes that were spun during spectral collection. The neat API spectrawere collected using 0.5 W of laser power and 128 co-added scans. Thecollection range was 3700-50 cm-1. These spectra were recorded using 4cm-1 resolution and Happ-Genzel apodization.

The intensity scale was normalized to 1 prior to peak picking. Peakswere manually identified using the Thermo Nicolet Omnic 7.3 software.Peak position was picked at the peak maximum, and peaks were onlyidentified as such, if there was a slope on each side; shoulders onpeaks were not included. For the neat API an absolute threshold of 0.015with a sensitivity of 77 was utilized during peak picking. The peakposition has been rounded to the nearest whole number using standardpractice (0.5 rounds up, 0.4 rounds down). Peaks with normalized peakintensity between (1-0.75), (0.74-0.30), (0.29-0) were labeled asstrong, medium and weak, respectively. It is expected that, sinceFT-Raman and dispersive Raman are similar techniques, peak positionsreported herein for FT-Raman spectra would be consistent with thosewhich would be observed using a dispersive Raman measurement, assumingappropriate instrument calibration. Utilizing the Raman method above,the variability associated with a spectral measurement is +/−2 cm⁻¹.

General Method 3. Solid State NMR

Solid state NMR (ssNMR) analysis was conducted at ambient temperatureand pressure on a Bruker-BioSpin CPMAS probe positioned into aBruker-BioSpin Avance III 500 MHz (¹H frequency) NMR spectrometer. Thepacked rotor was oriented at the magic angle and spun at 14.0 kHz. Thecarbon ssNMR spectrum was collected using a proton decoupledcross-polarization magic angle spinning (CPMAS) experiment. A phasemodulated proton decoupling field of 80-100 kHz was applied duringspectral acquisition. The cross-polarization contact time was set to 2ms and the recycle delay to 11 seconds. The number of scans was adjustedto obtain an adequate signal to noise ratio. The carbon spectrum wasreferenced using an external standard of crystalline adamantane, settingits upfield resonance to 29.5 ppm (as determined from neat TMS).

Automatic peak picking was performed using Bruker-BioSpin TopSpinversion 3.2 software. Generally, a threshold value of 5% relativeintensity was used to preliminary select peaks. The output of theautomated peak picking was visually checked to ensure validity andadjustments were manually made if necessary. Although specific ¹³C solidstate NMR peak values are reported herein there does exist a range forthese peak values due to differences in instruments, samples, and samplepreparation. This is common practice in the art of solid state NMRbecause of the variation inherent in peak values. A typical variabilityfor a ¹³C chemical shift x-axis value is on the order of plus or minus0.2 ppm for a crystalline solid. The solid state NMR peak heightsreported herein are relative intensities. Solid state NMR intensitiescan vary depending on the actual setup of the CPMAS experimentalparameters and the thermal history of the sample.

Example 1 Preparation of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureaimidazole Complex (1:1)

To a 250 mL reactor equipped with an overhead stirrer was added(2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-amine (3.24 g,14.1 mmol) (prepared according to Peng et al., Org. Lett. 2014,16:860-863) as a solution in water (63 mL) containing 20%dimethylsulfoxide. To the solution was added 4-methyl-2-pentanone(methyl isobutyl ketone, MIBK) (91 mL) followed byN-(4-cyanophenyl)-1H-imidazole-1-carboxamide 1H-imidazole complex (1:1)(5.18 g, 17.6 mmol) (prepared according to Peng et al.). The reactionwas heated at 45° C. for 1 hour. Diatomaceous earth (0.5 g, filter aid)was added and the biphasic mixture was filtered. The aqueous layer wasremoved and the organic layer was washed with water (33 mL). Imidazole(0.96 g, 14.1 mmol) was added along with additional 4-methyl-2-pentanone(18 mL). The solution was distilled to a final volume of 50 mL. Theresulting slurry was filtered and washed with 4-methyl-2-pentanone (13mL). The resulting solids were dried in a vacuum oven at 60° C. for 12 hto provide1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureaimidazole complex (1:1) (4.55 g, 10.3 mmol, 73% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 12.38 (bs, 1H); 12.07 (bs, 1H); 8.94 (s, 1H); 7.67 (d, J=8.4Hz, 2H); 7.65 (m, 1H); 7.58 (d, J=8.4 Hz, 2H); 7.55 (d, J=7.5 Hz, 1H);7.43 (bd, J=7.5 Hz, 1H); 7.14 (m, 2H); 7.02 (s, 2H); 6.75 (d, J=7.1 Hz,1 H); 4.08 (m, 1H); 3.63 (dd, J=10.4, 3.2 Hz, 1H); 2.90 (dt, HJ=11.9,4.2 Hz, 1H); 2.51 (p, J=1.8 Hz, 2H); 2.40 (td, J=11.7, 3.0 Hz, 1H); 2.06(s, 3H); 2.03 (m, 1H); 1.92 (m, 1H); 1.86 (m, 1H); 1.72 (m, 1H); ¹³C NMR(101 MHz, DMSO) δ 156.17, 154.34, 145.2, 135.6, 133.7, 122.3, 121.5,119.9, 118.9, 117.8, 111.7, 102.9, 59.1, 50.4, 44.2, 42.9, 36.5, 30.3.

Characterization of Alasdegib Imidazole Complex

PXRD Data

FIG. 4 shows PXRD data for the crystalline glasdegib imidazole complex(1:1), collected according to General Method 1.

Example 2 Preparation of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureamaleate (Form 1)

Into 1 L reactor, equipped with an overhead stirrer and High Shear WetMill (HSWM), was added1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureafree base (38.2 g; 102 mmol) (prepared as described by Munchhof et al.,Med. Chem., Lett, 2012, 3:106-111) and isopropanol (988 mL; 26 mL/g).The slurry was then heated to 60° C. to obtain a clear solution. Asolution of maleic acid in isopropanol was separately prepared bydissolving maleic acid (14.28 g; 123 mmol; 1.2 equiv) in isopropanol(115 mL; 3 mL/g). While the HSWM was running (3200-8500 rpm), 20% of themaleic acid solution was added and the reaction maintained until thesolution turned hazy. The HSWM was slowed down (3500 rpm) and the restof the maleic acid solution was added over 1 hour. After aging theslurry for 1 hour at 60° C., the batch was cooled to 10° C. over 2 hoursand granulated overnight. The solids were isolated by filtration, washedand dried at 60° C. The title compound (40.1 g; 801 mmol) was isolatedas a white to off-white powder in 80% yield. ¹H NMR (400 MHz, DMSO-d₆) δ9.00 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.62 (dd, J=6.0, 3.3 Hz, 2H), 7.57(d, J=8.8 Hz, 2H), 7.25 (dd, J=6.1, 3.2 Hz, 2H), 6.73 (d, J=7.5 Hz, 1H),6.08 (s, 2H), 4.40 (s, 1H), 3.91 (d, J=11.5 Hz, 1H), 3.44 (d, J=12.2 Hz,1H), 3.19 (s, 1H), 2.53 (s, 3H), 2.35 (d, J=13.2 Hz, 1H), 2.08 (d,J=13.3 Hz, 1H), 1.91 (q, J=12.4 Hz, 1H), 1.79 (q, J=12.4 Hz, 1H); ¹³CNMR (101 MHz, DMSO) δ 168.0, 154.7, 105.0, 145.3, 138.4, 135.6, 133.7,123.0, 119.9, 118.0, 115.9, 103.1, 57.9, 50.5, 41.9, 41.7, 34.6, 28.0.

Example 3 Preparation of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureamaleate (Form 1)

Into a 250 mL Flexy cube reactor equipped with an overhead stirrer, wasadded1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureaimidazole complex (1:1) (7 g, 15.8 mmol) and isopropanol (140 mL; 20mL/g of imidazole complex). The slurry was heated to 60° C. and helduntil a clear solution was obtained. A solution of maleic acid (34.8mmol, 2.2 equiv) in aq. isopropanol (1% w/w) was prepared separately.Thirty percent of the maleic acid solution was added and the mixture wasstirred for 5 min. Glasdegib maleate (77.6 mgs, 1%) was added as a seed,followed by the remainder of the maleic acid solution over 30 min. Afteraging at 60° C. for 30 min, the slurry was cooled to 20° C. over 60minutes and granulated for an additional 60 min. After sonicating for 3min, the slurry was filtered, washed with isopropanol (16 mL), followedby water washes (2×31 mL). The solids were dried in the oven at 60° C.for 12 hours to give glasdegib maleate (Form 1) (15.1 mmol, 7.40 g) as atan powder in 95.4% yield with >98% purity. ¹H NMR (400 MHz, DMSO-d₆) δ9.00 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.62 (dd, J=6.0, 3.3 Hz, 2H), 7.57(d, J=8.8 Hz, 2H), 7.25 (dd, J=6.1, 3.2 Hz, 2H), 6.73 (d, J=7.5 Hz, 1H),6.08 (s, 2H), 4.40 (s, 1H), 3.91 (d, J=11.5 Hz, 1H), 3.44 (d, J=12.2 Hz,1H), 3.19 (s, 1H), 2.53 (s, 3H), 2.35 (d, J=13.2 Hz, 1H), 2.08 (d,J=13.3 Hz, 1H), 1.91 (q, J=12.4 Hz, 1H), 1.79 (q, J=12.4 Hz, 1H); ¹³CNMR (101 MHz, DMSO) δ 168.0, 154.7, 105.0, 145.3, 138.4, 135.6, 133.7,123.0, 119.9, 118.0, 115.9, 103.1, 57.9, 50.5, 41.9, 41.7, 34.6, 28.0.

Characterization of Glasdeqib Maleate (Form 1)

PXRD Data

FIG. 1 shows PXRD data for the crystalline glasdegib maleate (Form 1),collected according to General Method 1. A list of PXRD peaks atdiffraction angles 2-Theta ° (°2θ)±0.2 °2θ and their relativeintensities is provided in Table 1. Characteristic PXRD peak positionsare indicated by an asterisk.

TABLE 1 PXRD peak list for glasdegib maleate (Form 1) (2-Theta °). AngleRelative °2θ ± 0.2 °2θ Intensity % 9.8 3 10.4 13 11.6* 34 12.1* 30 12.69 14.2 2 15.8 16 17.0* 42 17.3* 33 17.7* 22 18.0 10 18.4 13 19.6* 10020.9 3 21.3 11 22.1 8 23.0 7 23.9 5 24.3 14 24.7 7 25.0 6 25.3 8 25.8 5

FT-Raman Data

FIG. 2 shows FT-Raman spectrum for the crystalline glasdegib maleate(Form 1), collected according to General Method 2. A list of FT-Ramanpeaks (cm⁻¹) and qualitative intensities is provided in Table 2 incm⁻¹±2 cm⁻¹. Characteristic FT-Raman peaks (cm⁻¹) peaks are indicated byan asterisk. Normalized peak intensities are indicated as follows:w=weak; m=medium; s=strong.

TABLE 2 Full Raman Spectrum Peak list for glasdegib maleate (Form 1)Wave number Normalized cm⁻¹ ± 2 cm⁻¹ peak intensity  107 m  128 m  201 w 280 w  327 w  375 w  400 w  421 w  455 w  480 w  494 w  520 w  551 w 620* w  646 w  675 w  729 w  748 w  800 w  830* w  873 w  902 w  927 w 997* w 1014 w 1070 w 1113 w 1145 w 1175* m 1208* w 1233* w 1261* w1273* m 1320 w 1329 w 1387 w 1432* w 1444* w 1463 w 1490 w 1534* m 1589*w 1612* m 1691* w 2168 w 2219* s 2932 w 2955* w 2976* w 3013* w 3029* w3056 w 3116 w

ssNMR data

FIG. 3 shows the carbon CPMAS spectrum of crystalline glasdegib maleate(Form 1), which was collected according to General Method 3. Chemicalshifts are expressed in parts per million (ppm) and are referenced toexternal sample of solid phase adamantane at 29.5 ppm. A list of ssNMR¹³C chemical shifts (ppm) is provided in Table 3 in ppm±0.2 ppm.Characteristic ssNMR ¹³C chemical shifts (ppm) are indicated by anasterisk.

TABLE 3 ssNMR ¹³ C Chemical Shifts for glasdegib maleate (Form 1) (ppm)¹³ C Chemical Shifts Relative [ppm ± 0.2 ppm] Intensity (%) 27.6 47 36.149 42.7 95 50.7 49 57.8* 64 105.7 53 112.4 54 115.9 54 119.0 97 124.8 55126.2 54 132.9 100 134.8* 98 138.4 56 144.7* 97 148.3 59 154.6 53 171.192

Example 4 Representative Drug Product Formulation of Glasdegib Maleate(Form 1)

A representative immediate release (IR) formulation of crystallineglasdegib maleate (Form 1) is provided in Table 4. Typical ranges forexcipients in such formulations are provided in Table 5.

TABLE 4 Representative Composition of IR Tablet Quantity/unitcomposition (mg/tablet) Wt % glasdegib maleate Active Ingredient 32.76526.2 (Form 1) Microcrystalline Filler 58.157 46.5 Cellulose DibasicCalcium Filler 29.078 23.3 Phosphate Anhydrous Sodium StarchDisintegrant 3.750 3.0 Glycolate Magnesium Stearate Lubricant 0.625 0.5(intra-granular) Magnesium Stearate Lubricant 0.625 0.5 (extra-granular)Total Tablet Weight 125.000 mg 100

TABLE 5 Typical Ranges for IR Tablet Formulations composition Min. Wt %Max. Wt % glasdegib maleate Active Ingredient 16.383% 32.765% (Form 1)Microcrystalline Filler 41.156% 53.078% Cellulose Dibasic Calcium Filler20.578% 26.539% Phosphate Anhydrous Sodium Starch Disintegrant 3.000%3.000% Glycolate Magnesium Stearate Lubricant 1.000% 2.500%

PXRD Data

Table 6 provides a list of PXRD peaks at diffraction angles 2-Theta °(°2θ)±0.2 °2θ and their relative intensities for the drug productcontaining crystalline glasdegib maleate (Form 1), collected accordingto General Method 1. Characteristic PXRD peak positions are indicated byan asterisk.

TABLE 6 PXRD peak list for glasdegib maleate (Form 1) drug product(2-Theta °). Asterisked peak positions represent characteristic peaks.Angle Relative °2θ ± 0.2 °2θ Intensity % 3.6 22 4.7 12 5.4 13 9.1  7 9.7 9 (API) 10.4 16 (API) 11.5* 39 (API) 12.1* 27 (API) 12.6 16 (API) 13.117 14.3 19 (API) 14.9 21 15.8 32 (API) 16.3 23 17.0* 60 (API) 17.3* 42(API) 17.6* 37 (API) 18.0 24 (API) 18.4 25 (API) 19.6* 99 (API) 20.3 2420.8 28 (API) 21.3 35 (API) 22.2 57 22.6 57 23.8 29 24.2 27 (API) 24.722 25.3 22 25.5 22 26.6 83 27.2 100 (API)  28.2 32 (API) 28.5 31 28.9 2430.2 86 30.5 46 31.0 17 32.5 33 32.8 40 33.5 17 34.1 16 34.6 19 35.0 2035.4 16 36.0 23 37.3 16 37.7 16 38.3 14 39.1 16 25.3 22

Example 5 Preparation of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea(S)-mandelate Salt

1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureafree base (318 mg, 0.85 mmol) was dissolved into 10 mL of isopropanol ina scintillation vial fitted with a stir bar. The solution was heated to50° C. to ensure complete dissolution. To the solution was slowly addedS-(+)-mandelic acid (˜1.1 equiv) as a 30 mg/mL solution in isopropylalcohol. After addition of a small amount of (S)-mandelate salt seedcrystals, the solution became cloudy. The slurry was held at 50° C. for˜1 hour before being returned to room temperature and granulated for 12hours. The resulting solids were isolated by filtration using a #2Whatman filter and dried for 12 hours at 50° C. in a vacuum oven.Approximately 400 mg of glasdegib (S)-mandelate were prepared. The seedcrystals were obtained by precipitation from a mixture of glasdegib freebase, prepared as a stock solution in acetonitrile (˜30 mg/mL), andS-(+)-mandelic acid as a solution of THF, which was stirred at rtovernight after heating at 60° C. for ˜1 hour. The ¹H NMR spectra wasconsistent with the (S)-mandelate salt.

Characterization of Glasdegib (S)-mandelate Salt

The scaleup lot of the (S)-mandelate salt was analyzed by PXRD andDifferential Scanning calorimetry (DSC). PXRD was obtained on a BrukerD8 X-Ray powder diffractometer with GADDS C2 system. Samples werescanned from ˜6 to 38 degrees 2-theta for 60 seconds and oscillated 0.5mm about the center. DSC was obtained on a TA DSC Q1000. The sample washeated at 10° C./min from 25° C. to 300° C.

PXRD Data

FIG. 5 shows PXRD data for the crystalline glasdegib (S)-mandelate,collected according to General Method 1.

DSC

The DSC thermogram displayed a sharp endotherm at 216° C.

Example 6 Comparative Stability Data

Comparative chemical and physical stability data was generated fortablet cores comprising glasdegib dihydrochloride monohydrate(diHCl.H₂O) and glasdegib maleate (Form 1) stored at 50° C./75% RH for 6weeks. The tablet cores were prepared by dry granulation processing in aformulation composition comprising microcrystalline cellulose, dicalciumphosphate, sodium starch glycolate and magnesium stearate at an activedrug loading level of 5%. The tablet cores were stored in open dish (nopackaging) orientation in a 50° C./75% RH chamber and analyzed after 6weeks of storage. The analytical testing included HPLC/Purity analysisand solid state NMR (for solid form).

TABLE 7 %-(2S,4R)-Epimer Sample Initial 6 weeks @ Storage ssNMRDescription Level 50° C./75% RH Recommendations Observations GlasdegibNot 2.75% Desiccated storage Solid form dihydrochloride detectedrequired for drug conversion to monohydrate product; 15-25° C. amorphous(diHCl•H₂O) Glasdegib 0.024% 0.55% No special packaging Consistent withmaleate required (no desiccant the ingoing API (Form 1) required);15-25° C. solid form.

The primary degradation product monitored is the epimeric1-((2S,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea,which has the structure:

A statistically designed 21-day stability study was performed forglasdegib maleate tablets and glasdegib dihydrochloride tabletscontaining 5% active drug loading. The design of the study is based onwork in the literature that demonstrates the modeling degradationobserved of solid oral dosage forms. See Waterman et al., PharmaceuticalResearch, 24(4): 780-790 (2007). The tablets were stored in open glassbottles and exposed to various temperature, humidities and durations.

The recommended packaging for the glasdegib dihydrochloride monohydratetablets is HDPE/IS Bottle, with desiccant. The labeled storage conditionof this product is 15-25° C. Based on an accelerated stability studyfocusing on formation of the (2S,4R)-epimer with a target specificationlimit of NMT 0.5%, the shelf-life predicted for the glasdegibdihydrochloride monohydrate (60 cc HDPE bottle, 30 count tablets) at 25°C./60% RH is approximately 5 years with dessicant, and less than 2 yearsif stored without desiccant.

The recommended packaging for the glasdegib maleate tablets is HDPE/ISBottle and no desiccant is required. The labeled storage condition ofthis product is 15-25° C. Based on the accelerated stability studyfocusing on formation of the (2S,4R)-epimer with a target specificationlimit of NMT 0.5%, the shelf-life predicted for glasdegib maleate (60 ccHDPE bottle, 30 count tablets) at 25° C./60% RH is more than 6 yearsstored without desiccant.

Example 7 Comparative Thermal Stability Data

Comparative thermal stability data was generated for glasdegibdihydrochloride monohydrate (diHCl.H₂O) and glasdegib maleate (Form 1).Differential Scanning calorimetry (DSC) measurements were performed withDiscovery DSC (TA instruments) equipped with a refrigerated coolingaccessory. All the experiments were performed in standard/Tzero aluminumpans. The cell constant was determined using indium and temperaturecalibration was performed using indium and tin as standards. All themeasurements were done under continuous dry nitrogen purge (50 mL/min).Approximately 2-5 mg of solid sample was weighed into a standard/Tzeroaluminum pan, sealed non-hermetically and heated from 25° C. to 250 ° C.at 10° C./min heating rate. The experimental data were analyzed usingcommercially available software (TA Universal Analysis 2000/Triossoftware, TA Instruments).

Based on the observed thermal stability data, the diHCl monohydratesolid form may be unstable under certain isolation and storageconditions due to the low dehydration temperature. The maleate formappears stable across a wide temperature range. The high level of formstability for the maleate salt may provide improved control inprocessing, handling, manufacture and storage for this form.

TABLE 8 Comparative thermal stability data Form Thermal StabilityRemarks Glasdegib maleate Stable up to 207° C. (Form 1) (melting onset)Glasdegib Stable up to 50° C. Broad endotherm at 50° C. dihydrochloridecoincides with loss of water monohydrate

Modifications may be made to the foregoing without departing from thebasic aspects of the invention. Although the invention has beendescribed in substantial detail with reference to one or more specificembodiments, those of ordinary skill in the art will recognize thatchanges may be made to the embodiments specifically disclosed in thisapplication, and yet these modifications and improvements are within thescope and spirit of the invention.

What is claimed is:
 1. A crystalline form of1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)ureamaleate, having the structure:


2. The crystalline form of claim 1, having a powder X-ray diffractionpattern comprising peaks at 2θ values of: 11.6, 12.1 and 19.6 °2θ±0.2°2θ.
 3. The crystalline form of claim 1, having a powder X-raydiffraction pattern comprising peaks at 2θ values of: 11.6, 12.1, 17.0,17.7 and 19.6 °2θ±0.2 °2θ.
 4. The crystalline form of claim 1, having aRaman spectrum comprising wavenumber (cm⁻¹) values of: 2219 cm⁻¹±2 cm⁻¹.5. The crystalline form of claim 1, having a Raman spectrum comprisingwavenumber (cm⁻¹) values of: 1612 cm⁻¹±2 cm⁻¹.
 6. The crystalline formof claim 1, having a Raman spectrum comprising wavenumber (cm⁻¹) valuesof: 1612 and 2219 cm⁻¹+2 cm⁻¹.
 7. The crystalline form of claim 1,having a Raman spectrum comprising wavenumber (cm⁻¹) values of: 1534,1612 and 2219 cm⁻¹+2 cm⁻¹.
 8. The crystalline form of claim 1, having aRaman spectrum comprising wavenumber (cm⁻¹) values of: 1175, 1534, 1612and 2219 cm⁻¹±2 cm⁻¹.
 9. The crystalline form of claim 1, having a ¹³Csolid state NMR spectrum comprising resonance (ppm) values of: 148.3ppm±0.2 ppm.
 10. The crystalline form of claim 1, having a ¹³C solidstate NMR spectrum comprising resonance (ppm) values of: 57.8, 134.8 and148.3 ppm±0.2 ppm.
 11. The crystalline form of claim 1, having a ¹³Csolid state NMR spectrum comprising resonance (ppm) values of: 57.8,134.8, 144.7 and 148.3 ppm±0.2 ppm.
 12. The crystalline form of claim 1,having: (a) a powder X-ray diffraction pattern comprising a peak at a 2θalue of: 11.6 and 12.1 °2θ±0.2 °2θ; and (b) a Raman spectrum comprisingwavenumber (cm⁻¹) values of: 1612 and 2219 cm⁻¹±2 cm⁻¹ .
 13. Thecrystalline form of claim 1, having: (a) a powder X-ray diffractionpattern comprising a peak at a 2θ value of: 11.6 and 12.1 °2θ±0.2 °2θ;(b) a Raman spectrum comprising wavenumber (cm⁻¹) values of: 1612 and2219 cm⁻¹±2 cm⁻¹; and (c) a ¹³C solid state NMR spectrum comprising aresonance (ppm) value of: 148.3 ppm±0.2 ppm.
 14. The crystalline form ofclaim 1, having: (a) a Raman spectrum comprising wavenumber (cm⁻¹)values of: 1612 and 2219 cm⁻¹±2 cm⁻¹; and (b) a ¹³C solid state NMRspectrum comprising a resonance (ppm) value of: 148.3 ppm±0.2 ppm. 15.The crystalline form of claim 1, having: (a) a powder X-ray diffractionpattern comprising a peak ata 2θ value of: 11.6 and 12.1 °2θ±0.2 °2θ;and (b) a ¹³C solid state NMR spectrum comprising a resonance (ppm)value of: 148.3 ppm±0.2 ppm.
 16. The crystalline form of claim 1,having: (a) a powder X-ray diffraction pattern comprising a peak at a 2θvalue of: 19.6 °2θ±0.2 °2θ; (b) a Raman spectrum comprising wavenumber(cm⁻¹) values of: 2219 cm⁻¹±2 cm⁻¹; and (c) a ¹³C solid state NMRspectrum comprising a resonance (ppm) value of: 148.3 ppm±0.2 ppm.
 17. Apharmaceutical composition comprising the crystalline form of claim 1,and a pharmaceutically acceptable carrier or excipient.